We present a Surrogate (semiempirical) Model for prediction of protein adsorption onto the surfaces of biodegradable polymers that have been designed for tissue engineering applications. The protein used in these studies, fibrinogen, is known to play a key role in blood clotting. Therefore, fibrinogen adsorption dictates the performance of implants exposed to blood. The Surrogate Model combines molecular modeling, machine learning and an Artificial Neural Network. This novel approach includes an accounting for experimental error using a Monte Carlo analysis. Briefly, measurements of human fibrinogen adsorption were obtained for 45 polymers. A total of 106 molecular descriptors were generated for each polymer. Of these, 102 descriptors were computed using the Molecular Operating Environment (MOE) software based upon the polymer chemical structures, two represented different monomer types, and two were measured experimentally. The Surrogate Model was developed in two stages. In the first stage, the three descriptors with the highest correlation to adsorption were determined by calculating the information gain of each descriptor. Here a Monte Carlo approach enabled a direct assessment of the effect of the experimental uncertainty on the results. The three highest-ranking descriptors, defined as those with the highest information gain for the sample set, were then selected as the input variables for the second stage, an Artificial Neural Network (ANN) to predict fibrinogen adsorption. The ANN was trained using one-half of the experimental data set (the training set) selected at random. The effect of experimental error on predictive capability was again explored using a Monte Carlo analysis. The accuracy of the ANN was assessed by comparison of the predicted values for fibrinogen adsorption with the experimental data for the remaining polymers (the validation set). The mean value of the Pearson correlation coefficient for the validation data sets was 0.54 +/- 0.12. The average root-mean-square (relative) error in prediction for the validation data sets is 38%. This is an order of magnitude less than the range of experimental values (i.e., 366%) and compares favorably with the average percent relative standard deviation of the experimental measurements (i.e., 17.9%). The effects of each of the user-defined parameters in the ANN were explored. None were observed to have a significant effect on the results. Thus, the Surrogate Model can be used to accurately and unambiguously identify polymers whose fibrinogen absorption is at the limits of the range (i.e., low or high) which is an essential requirement for assessing polymers for regenerative tissue applications.